(1) Field of the Invention
The present invention relates to the preparation of novel 4-cyano-3-hydroxybutanoyl hydrazides which are intermediates to the preparation of medicinally important chiral compounds particularly (R)-3-hydroxy-4-trimethylaminobutyric acid (L-carnitine) and (R)-4-amino-3-hydroxy butyric acid (GABOB). In particular the present invention relates to the preparation of chiral compounds.
(2) Description Of Related Art
(R)-3-hydroxy-4-trimethylaminobutyric acid (L-carnitine 1 and (R)-4-amino-3-hydroxy-butyric acid (GABOB) 2 (FIGS. 1A and 1B) have a very high level of medical significance. L-carnitine is a very important intermediate in lipid biosynthesis. It functions as a carrier for transporting fatty acids into mitochondria for oxidation. Since fatty acid oxidation is a critical step by which cells derive energy, carnitine is important for cellular energetics. Deficiencies in the biosynthesis of L-carnitine lead to severe neurological problems. The two major uses of L-carnitine are in sports medicine and infant nutrition. There are several medical indications for which L-carnitine can be prescribed (Goa, K. L., et al. Drugs 34, 1 (1987); Guarnieri, G., et al., Amer. J. Clin. Nutr. 33, 1489 (1980); and Thomsen, J. H., et al., Amer. J. Cardiol. 33, 300 (1979)). (R)-4-Amino-3-hydroxy-butyric acid (GABOB) is a well known drug substance that functions as an agonist of gamma aminobutyric acid (GABA). It has been demonstrated to be effective in managing a variety of clinical conditions including schizophrenia and other character-based illnesses (Chapoy, P. R., et al., New Engl. J. Med. 303, 1389 (1980); and Takano, S., et al., Tetrahedron Lett, 28, 1783 (1987)), epilepsy and other illnesses that result in severe convulsions (Pinelli, P., Farmaco, Ed. Sci. 25, 187 (1970); and Demaio, D., et al., Acta Neurol. 16, 366 (1961)). Its use for the correction of some clinical conditions observed in children has also been explored (Buscaino, G. A., et al., Acta Neurol. 16, 748 (1961); and Comber, R. N., et al., J. Org. Chem. 52:2311 (1987)), fermentation (Fuganti, C., et al., Tetrahedron Lett, 27: 2061 (1986); Kulla, H. G., Chimia, 45, 81 (1991); Kasai, N., et al., Tetrahedron Lett. 33, 1211 (1992); Hashiguchi, S., et al., Synthesis 403 (1992); Lu, Y, et al., Tetrahedron Asymmetry 1 707 1990); Bianchi, D., et al., J. Org. Chem. 53, 104 (1988); Gopalan, A. S., et al., Tetrahedron Lett. 25, 5235 (1984)), asymmetric synthesis from natural products (Bols, M., et al., Tetrahedron Lett. 48:319 (1992); Bellamy, F. D., et al., Tetrahedron Lett, 31, 7323 (1990); Rajashekhar, B., et al., J. Org. Chem. 50, 5480 (1985); Bose, D. S., et al., Synth. Commun. 19, 3313 (1989); Pellegata, R., et al., Tetrahedron Lett. 41, 5607 (1985); Bock, K., et al., Acta Chem. Scand. Ser. B37, 341 (1983); Jung, M. E., et al., J. Am. Chem. Soc. 102, 6304 (1980)), and catalytic asymmetric synthesis (Kolb, H. C., et al., Tetrahedron Asymmetry 4, 133 (1993); Bubnov, Y. N., et al., Mendeleev Commun. 86 (1992); Braun, M., et al., Synthesis, 856 (1989); Rossiter, B. E., et al., J. Org. Chem. 49, 3707 (1984); Kabat, M. M., et al., Tetrahedron Asymmetry 8 2663 (1997); Lohray, B. B., et al., Tetrahedron Asymmetry 7, 2411 (1997); Bernabei, I., et al., Chem. Eur. J. 2, 826 (1996); Kitamura, M., et al., Tetrahedron Lett., 29, 1555 (1988); Sakuraba, S., et al., Chem. Pharm. Bull, 43, 738 (1995)). There is still a need, however, for straightforward syntheses that have significant practical value.
(S)-3-Hydroxy-.gamma.-butyrolactone 3 (FIG. 1C) is a 4-carbon chiral intermediate that can be obtained in high yield and very high chiral purity from a variety of carbohydrate building blocks including lactose, maltose and maltodextrins (Hollingsworth, R. I., Biotech. Ann. Rev. 2, 281 (1996); Huang, G., et al., Tetrahedron, 54 1355 (1998); and Hollingsworth, R. I., U.S. Pat. No. 5,292,939 (1994)). The functionalities present in this molecule make it easily amenable to conversion to carnitine and GABOB by placing a trimethylammonium group in the 4-position after ring opening the lactone with hydrogen bromide to form the 4-bromo acid 3A (FIG. 1E) and then displacing the bromo group with trimethylamine. However, the configuration at the 3-position is not the desired one. Synthesizing these molecules with the correct configuration from (S)-3-hydroxy-.gamma.-butyrolactone requires inversion of the 3-hydroxyl group or some equivalent transformation. Because of its position relative to the carbonyl group, attempts at inverting the 3-hydroxyl group by activation and displacement readily leads to elimination to yield 2-(5H) furanone. The alcohol group could not be modified even under the mildest of basic conditions. It was therefore necessary to provide an alternative to the inversion reaction.